Local anesthetic methods and kits

ABSTRACT

Methods of reversing local anesthesia are disclosed. The methods comprise administering a local anesthetic and alpha adrenergic receptor agonist to induce local anesthesia followed by reversing anesthesia with a low dose of an alpha adrenergic receptor antagonist. Also disclosed are kits comprising a local anesthetic, an alpha adrenergic receptor agonist and a low dose of an alpha adrenergic receptor antagonist.

FIELD OF THE INVENTION

[0001] The invention is in the field of medicinal chemistry. Theinvention relates in particular to a method of reversing localanesthesia induced by a local anesthetic and an alpha-adrenergicagonist, comprising administering an effective low dose of analpha-adrenergic antagonist.

RELATED ART

[0002] Local anesthesia is widely used by dentists to provide painrelief to patients during dental procedures. To provide pain relief, adrug formulation containing a local anesthetic compound such aslidocaine is injected into the gum tissue surrounding the tooth or teethon which the dental procedure is to be performed. There are short-actingand long-lasting local anesthetic drug formulations. Short-acting localanesthetic drug formulations contain lidocaine or a related localanesthetic drug dissolved in saline or other suitable injection vehicle.Typically, local anesthesia with short-acting local anesthetics lastsapproximately 20-30 minutes, which is not long enough for many dentalprocedures. To obtain long-lasting local anesthesia, dentists often uselidocaine or other local anesthetic formulations which, in addition tothe local anesthetic drug itself, contain low concentrations ofepinephrine or another adrenergic receptor agonist such aslevonordefrin. More than 90% of the local anesthesia proceduresperformed by dentists involve local anesthetic formulations containingalpha-adrenergic receptor agonists. The vasoconstrictor is necessarybecause local anesthetics without vasoconstrictor are too short-actingfor most dental procedures. The added epinephrine stimulatesalpha-adrenergic receptors on the blood vessels in the injected tissue.This hag the effect of constricting the blood vessels in the tissue. Theblood vessel constriction causes the local anesthetic to stay in thetissue much longer, resulting in a large increase in the duration of theanesthetic effect (from 20 minutes for the short-acting formulation to3-6 hours for the long-lasting formulation). A major problem with theuse of epinephrine-containing local anesthetics is soft-tissueanesthesia (lip, cheek, tongue) which usually lasts many hours longerthan anesthesia and analgesia of the tooth pulp. Tooth pulp anesthesiaand analgesia are the desired effects of local anesthesia from a dentalprocedural perspective while soft-tissue anesthesia is usually anundesirable side effect. Soft tissue anesthesia results in a number ofproblems and inconveniences, such as a prolonged and uncomfortablefeeling of numbness in and around the mouth, inability to smile,difficulty eating, drinking and swallowing, loss of productivity bymissing work hours or meetings etc. Lingering soft-tissue anesthesia canbe the cause of injuries due to biting of the tongue or lips. Lingeringsoft-tissue anesthesia can also result in loss of productivity due tomissed work hours or meetings etc. Furthermore, lingering soft-tissueanesthesia is an inconvenience and it is perceived as an annoyance bymany patients. Lingering soft-tissue anesthesia can lead to injuryespecially in children who often bite into the anesthetized tissue outof curiosity. It would therefore be desirable to have a drug that couldbe used at will by dentists to rapidly reverse local anesthesia after itis no longer needed

[0003] U.S. Pat. No. 4,659,714 discloses a method of prolonging localanesthesia by coadministering a vasoconstrictor, in particular, avasoconstrictor that acts upon the alpha-adrenergic receptor sites ofthe blood vessel walls. The '714 patent also discloses the subsequentadministration of an alpha-adrenergic receptor antagonist to causereduction of the prolonged anesthesia effect. Included within the groupof alpha-adrenergic receptor antagonists described in this patent arephentolamine mesylate. However, the examples make reference to theadministration of “phentolamine.” It is much more likely that what wasadministered was phentolamine mesylate since phentolamine mesylate isFDA approved and readily soluble in water. In contrast, phentolamine isnot FDA approved and is relatively insoluble in water.

[0004] As shown in Example 1, Table 1, 0.5-1.5 mg of “phentolamine” wasadministered to groups of patients which were pretreated with lignocaineadmixed with epinephrine. The results in Table 1 show a reduction in theduration of anesthesia with increasing amounts of “phentolamine.” InExample 2, 2 mg of “phentolamine” was administered. In Example 3, fourinjections of 1 mg each (4 mg total) of “phentolamine” wereadministered. In Example 4, four injections of 1 mg each (4 mg total) of“phentolamine” were administered.

[0005] The drug doses of “phentolamine” described in the '714 patent(0.5-4 mg) overlap the doses of phentolamine mesylate that are approvedby the FDA for the systemic treatment of high blood pressure in patientswith pheochromocytoma (total dose of 5 mg in a solution of 2.5-5 mg/ml). Since those doses are normally intended for systemic treatment ofhigh blood pressure, those high dose levels can cause severe sideeffects when used in healthy, normal people. The package insert of thephentolamine-mesylate product states the following side effect warning:“Myocardial infarction, cerebrovascular spasm, and cerebrovascularocclusion have been reported to occur following the administration ofphentolamine, usually in association with marked hypotensive episodes.”Thus, the drug doses taught by the '714 patent for the reversal of localanesthesia may cause unacceptable side effects, precluding the use ofthis product for anesthesia reversal in healthy normal subjects in adentist's office.

[0006] It has now been discovered that a highly effective localanesthesia reversal can be obtained by injections of much lowerconcentrations of phentolamine-mesylate than is disclosed in the '714patent. It has been found that a solution containing only 0.05 mg /ml ofphentolamine-mesylate can rapidly reverse the effect of a localanesthetic containing an alpha adrenergic receptor agonist. Thisphentolamine-mesylate drug concentration is 20-100 times lower than thephentolamine-mesylate drug concentration taught by the '714 patent. Theadvantage is that, at such low phentolamine-mesylate drugconcentrations, no systemic side effects such as myocardial infarctionand cerebrovascular spasm will be observed. This allows the safe andeffective use of phentolamine-mesylate for local anesthesia reversalwithout causing life-threatening or other untoward side effects. Indeed,in a human clinical efficacy study using a low-concentration-formulationof phentolamine-mesylate, a highly effective anesthesia reversal wasobserved without any side-effects whatsoever. Thus, this inventionconstitutes a crucial improvement of the local anesthesia reversalmethod taught by the '714 patent.

SUMMARY OF THE INVENTION

[0007] The present invention provides compositions and formulations oflow concentrations of phentolamine-mesylate and other alpha adrenergicreceptor antagonists and use thereof for reversing the effects oflong-lasting local anesthetic agents containing alpha-adrenergicreceptor agonists.

[0008] In particular, the invention relates to a method of providinglocal anesthesia to a mammal, comprising:

[0009] (a) administering to the mammal in need thereof an anestheticagent and an alpha adrenergic receptor agonist to the site to beanesthetized, wherein said anesthetic agent is administered in an amounteffective to provide local anesthesia and said alpha adrenergic receptoragonist is administered in an amount effective to constrict the bloodvessels at the site and prolong the local anesthesia, and then

[0010] (b) administering a low dose of an alpha adrenergic receptorantagonist to said site to reduce the prolongation.

[0011] In a preferred embodiment, the invention relates to a method ofproviding local anesthesia to a human, comprising:

[0012] (a) administering to a human in need thereof by injection to thesite to be anesthetized a solution comprising polocaine andlevonordefiin, wherein said polocaine is administered in an amounteffective to provide local anesthesia and said levonerdefrin isadministered in an amount effective to constrict the blood vessels atthe site and prolong the local anesthesia, thereby producing localanesthesia at said site,

[0013] (b) carrying out a medical procedure on the human, and then

[0014] (c) administering phentolamine mesylate at said site at aconcentration of about 0.05 mg /ml or less to reduce the prolongation.

[0015] The invention also relates to a method of enhancing the survivalof a tissue graft, comprising

[0016] (a) administering to a mammal undergoing a tissue graft ananesthetic agent and an alpha adrenergic receptor agonist to the site ofthe tissue graft, wherein said anesthetic agent is administered in anamount effective to provide local anesthesia and said alpha adrenergicreceptor agonist is administered in an amount effective to constrict theblood vessels at the site and prolong the local anesthesia,

[0017] (b) performing the tissue graft procedure, and then

[0018] (c) administering an alpha adrenergic receptor antagonist to saidsite to reduce the prolongation and enhance the tissue graft survival.

[0019] The invention also relates to a method of providing a regionalanesthetic block to a mammal, comprising:

[0020] (a) administering to the mammal in need thereof an anestheticagent and an alpha adrenergic receptor agonist in the site to receivethe anesthetic block, wherein said anesthetic agent is administered inan amount effective to provide local anesthesia and said alphaadrenergic receptor agonist is administered in an amount effective toconstrict the blood vessels in the site and prolong the anestheticblock, and then

[0021] (b) administering an alpha adrenergic receptor antagonist to saidsite to reduce the prolongation.

[0022] The invention also relates to a kit comprising a carrier meanshaving in close confinement therein two or more container means, whereina first container means contains an anesthetic agent and optionally analpha adrenergic receptor agonist and a second container means containsa low dose of an alpha adrenergic receptor antagonist.

DESCRIPTION OF PREFERRED EMBODIMENTS

[0023] The invention relates to a method of providing local anesthesiato a mammal, comprising:

[0024] (a) administering to the mammal in need thereof an anestheticagent and an alpha adrenergic receptor agonist to the site to beanesthetized, wherein said anesthetic agent is administered in an amounteffective to provide local anesthesia and said an alpha adrenergicreceptor agonist is administered in an amount effective to constrict theblood vessels at the site and prolong the local anesthesia, and then

[0025] (b) administering a low dose of an alpha adrenergic receptorantagonist to said site to reduce the prolongation.

[0026] The anesthetic agent and alpha adrenergic receptor agonist may beadministered together as part of a unitary pharmaceutical composition oras part of separate pharmaceutical compositions so long as the alphaadrenergic receptor agonist acts to constrict the blood vessels in thevicinity of where the anesthetic agent has been administered to resultin a prolonging of anesthesia. In a preferred embodiment, the anestheticagent and alpha adrenergic receptor agonist are administered together insolution. The anesthetic agent and alpha adrenergic agonist may beadministered by injection, by infiltration or by topical administration,e.g. as part of a gel or paste.

[0027] In a preferred embodiment, a solution comprising the anestheticagent and alpha adrenergic receptor agonist is administered by injectiondirectly into the site to be anesthetized, e.g. prior to a dentalprocedure.

[0028] Examples of local anesthetics that may be used in the practice ofthe invention include without limitation lidocaine, polocaine,lignocaine, xylocaine, novocaine, carbocaine, etidocaine, procaine,prilocaine, bupivacaine, cinchocaine and mepivacaine.

[0029] Examples of alpha adrenergic receptor agonists that can be usedaccording to the invention include catecholamines and catecholaminederivatives. Particular examples include without limitationlevonordefrin, epinephrine, and norepinephrine.

[0030] Examples of alpha adrenergic receptor antagonists that can beused in the practice of the invention include without limitationphentolamine, phentolamine hydrochloride, phentolamine mesylate,tolazoline, yohimbine, rauwolscine, doxazosine, labetolol, prazosine,tetrazosine and trimazosine. Phentolamine-mesylate is approved by theFDA for the treatment of hypertension in patients with pheochromocytoma,for the treatment of dermal necrosis and sloughing following accidentalextravasation of norepinephrine, and for the diagnosis ofpheochromocytoma (phentolamine blocking test). The drug is supplied invials containing 5 mg of drug substance which may be dissolved inphysiological saline or other pharmaceutically acceptable carrier.

[0031] In order to reverse the local anesthesia after a medicalprocedure according to the present invention, the alpha adrenergicreceptor antagonist is administered at a low dose, i.e. at a dose thatdoes not cause side effects, i.e. at or below about 0.25 mg per dose foradults (at or below about 0.0036 mg /kg) or 0.1 mg per dose forchildren, more preferably, below about 0.1 mg per dose for adults (belowabout 0.0014 mg /kg) or 0.04 mg per dose for children, most preferably,at about 0.08 mg per dose for adults (about 0.001 mg /kg) or about 0.032mg per dose for children, of phentolamine mesylate or a molar equivalentof another adrenergic receptor antagonist. In a preferred embodiment,the alpha adrenergic receptor antagonist is present at a concentrationof from about 0.001 mg /ml to about 0.25 mg /ml, more preferably, about0.05 mg /ml to about 0.1 mg /ml.

[0032] The alpha adrenergic receptor antagonist may be administered byinjection into the site of anesthesia, by infiltration or by topicaladministration. In a preferred embodiment, the alpha adrenergic receptorantagonist is administered to mucosal tissue. In this embodiment, thealpha adrenergic receptor antagonist may be applied to the site in theform of an impregnated wafer, pellet or cotton ball, whereby theantagonist is taken up by the mucosal tissue resulting in reversal ofthe anesthesia. In another embodiment, the alpha adrenergic receptorantagonist is administered to the site of a regional anesthetic block toreverse the block, e.g. by injection or infiltration into the site. In apreferred embodiment, the alpha adrenergic receptor antagonist isadministered via a cannula into the epidural space of an animal toreverse epidural anesthesia.

[0033] Examples of medical procedures that may be carried out accordingto the present invention include, without limitation, both major andminor surgery, dental procedures, cosmetic surgery, tissue grafting(e.g. hair and bone grafting) and cesarean section. In one embodiment,reversal of anesthesia according to the present invention is carried outby medical trainees to mitigate any mistakes that are made, and whichmay lead to the loss of extremities such as fingers, as well as ears andtips of noses.

[0034] Hyaluronidase, an enzyme which enhances the diffuision of drugswithin tissues, may be administered together with the alpha adrenergicreceptor antagonist. The hyaluronidase and alpha adrenergic receptorantagonist may be administered together as part of a unitarypharmaceutical composition or as part of separate pharmaceuticalcompositions, so long as the hyaluronidase and alpha adrenergic receptorantagonist are administered to the site where anesthesia is to bereversed and are present in amounts effective to enhance the diffusionof the alpha adrenergic receptor antagonist and to reverse theanesthesia, respectively. The hyaluronidase is administered one or moretimes into the site of anesthesia. In general, about 1.5 U to about 200Uof hyaluronidase is administered in one or more injections. In a mostpreferred embodiment, about 200 U of hyaluronidase is administered byinjection into the site. Those of ordinary skill in the art candetermine optimal amounts of hyaluronidase with no more than routineexperimentation.

[0035] When performing hair grafts, the surgeon often injects ananesthetic and epinephrine to reduce bleeding and provide a clear visionof the site. According to Bernstein, R. M. and Rassman, W. R., HairTransplant Forum International 10:39-42 (2000), the usefulness ofepinephrine in hair graft procedures is limited by a number of factorsincluding post-operative telogen effluvium when epinephrine is used inlarge transplant sessions. In addition, when adrenaline is added to anarea whose blood supply is already compromised by a large number ofrecipient sites, the tissue may not receive enough oxygen. Although notproven, according to Bernstein and Rassman it is likely that epinephrineinfiltration into the recipient area is a contributing factor in thedevelopment of the “central necrosis” that has occasionally beenreported during hair transplantation. Furthermore, it is possible thatthe intense vasoconstrictive action of epinephrine may contribute to thedecreased graft survival. Thus, according to the present invention, onemay achieve enhanced tissue graft survival in a method comprising

[0036] (a) administering to a mammal undergoing a tissue graft ananesthetic agent and an alpha adrenergic receptor agonist to the site ofthe tissue graft, wherein the anesthetic agent is administered in anamount effective to provide local anesthesia and the an alpha adrenergicreceptor agonist is administered in an amount effective to constrict theblood vessels at the site and prolong the local anesthesia,

[0037] (b) performing the tissue graft procedure, and then

[0038] (c) administering an alpha adrenergic receptor antagonist to saidsite to reduce the prolongation and enhance the tissue graft survival.

[0039] In a preferred embodiment, the tissue graft is a hair graft. Inanother preferred embodiment, a low dose of alpha adrenergic receptorantagonist is administered to the site to avoid untoward side effects.

[0040] Such hair grafts include skin flaps containing a plurality ofhair cells and single transplanted hair cell follicles. Typically, suchhair grafts are obtained from a site on the animal that has activelygrowing hair. According to the present invention, an alpha adrenergicreceptor antagonist is administered after a hair graft procedure toreverse the local anesthesia and reduce post-operative telogen effluvium(shedding of hair) and survival of the skin flap.

[0041] In another embodiment, hyaluronidase may be administered to thetissue graft site to increase survival of the graft. According toPimentel, L. A. S. and Goldenburg, R. C. d. S, Revista da SoociedadeBrasileira de Cirurgia Plastica 14 (1999), the local administration ofhyaluronidase increases skin flap survival. According to the authors,hyaluronidase is an enzyme that reduces or prevents tissue injurypresumably by causing the rapid diffusion of extravasated fluids todistant areas, thus allowing a better turnover of nutrients. Thehyaluronidase is generally injected one or more times into the site ofthe hair graft. Similarly, the present invention can be used to improvesurvival of other engrafted tissues or bone in any graft surgicalprocedure where a local anesthetic and an alpha adrenergic receptoragonist is used minimize bleeding during the surgery and wheresubsequent rapid reperfusion of tissue is desired in order to increasegraft survival.

[0042] In a further embodiment, an alpha adrenergic receptor antagonistis administered after a regional anesthetic block to reverse the block.Epidural anesthesia is commonly administered to provide a regionalanesthetic block in a number of medical procedures including childbirth, cesarean section, surgery to the pelvis and the like. Prolongedepidural anesthesia has many untoward side effects, including prolongedparalysis, inability to voluntarily urinate, and hypotension. Typically,the anesthesiologist injects into the epidural space an equal volume ofsaline in an effort to dilute the anesthetic and reduce the anesthesia.

[0043] The present invention solves the side effect problems byproviding for on demand reversal of the anesthesia without the need forinjecting large volumes of saline. In this embodiment, the inventionrelates to a method of providing a regional anesthetic block to amammal, comprising:

[0044] (a) administering to a mammal in need thereof an anesthetic agentand an alpha adrenergic receptor agonist in the site to receive theanesthetic block, wherein the anesthetic agent is administered in anamount effective to provide local anesthesia and the alpha adrenergicreceptor agonist is administered in an amount effective to constrict theblood vessels in the site and prolong the local anesthesia, and then

[0045] (b) administering an alpha adrenergic receptor antagonist to thesite to reduce the prolongation.

[0046] In a preferred embodiment, a low dose of the alpha adrenergicreceptor antagonist is administered. In another preferred embodiment,the anesthetic block is epidural anesthesia and the site of the block isthe epidural space. The invention has application to reversal of otherblocks as well including brachial plexus and femoral blocks.

[0047] In another embodiment, hyaluronidase is administered togetherwith the alpha adrenergic receptor antagonist to enhance the diffusionof the alpha adrenergic receptor antagonist within the site of theblock, e.g. the epidural space, and speed reversal of the anesthesia.

[0048] The invention also relates to a kit comprising a carrier meanssuch as a carton or box having in close confinement therein two or morecontainer means such as carpules, vials, tubes, jars and the like. Afirst container means contains an anesthetic agent and optionally analpha adrenergic receptor agonist and a second container means containsa low dose of an alpha adrenergic receptor antagonist. Alternatively,the alpha adrenergic receptor agonist may be present in a separatecontainer means. A further container means may contain hyaluronidase.Alternatively, the hyaluronidase is in the same container means as thealpha adrenergic receptor antagonist. In a preferred embodiment, theanesthetic agent, alpha adrenergic receptor agonist, alpha adrenergicreceptor antagonist and, optionally, the hyaluronidase are present in1.8 mL carpules that fit into a standard dental local anestheticsyringe. Such carpules are available commercially from a variety ofsuppliers, e.g. Henry Schein, Port Washington, N.Y. In this embodiment,a carpule containing the local anesthetic and alpha adrenergic receptoragonists is placed into the syringe, and the mixture is injected. Thecarpule may then be removed and a second carpule inserted which containsthe alpha adrenergic receptor antagonist and, optionally, thehyaluronidase.

[0049] The anesthetic agent, vasoconstrictor, alpha adrenergic receptorantagonist and, optionally, the hyaluronidase may be present insolution, preferably, a sterile solution, optionally containing saltsand buffers, or as part of a gel or paste for topical administration.See U.S. Pat. No. 4,938,970 and Remington's Pharmaceutical Sciences, A.Osol (ed.), 16th Edition, Mack Publishing Co., Easton, Pa. (1980).

[0050] Mammals which may be treated according to the present inventioninclude all mammals that may experience the beneficial effects of thepresent invention. Such mammals include without limitation humans andveterinary mammals such as cattle, pigs, sheep, horses, dogs, and cats.When applied to children and veterinary animals, the prompt reversal ofanesthesia inhibits the child or animal from tearing open fresh sutures.

[0051] The following examples are illustrative, but not limiting, of themethod and compositions of the present invention. Other suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art are within the spirit and scope ofthe invention.

EXAMPLES Study Rationale and Purpose

[0052] Local anesthesia is widely used by dentists to effect anesthesiaduring dental procedures. Local anesthetics often containalpha-adrenergic receptor agonists to cause vasoconstriction therebyprolonging anesthesia. The vasoconstrictor is necessary because localanesthetics without vasoconstrictor are too short-acting for most dentalprocedures. On the other hand, in many instances the prolonged localanesthetic effect lasts much longer than required for many dentalprocedures. It would be desirable to have a drug that could be used atwill to rapidly reverse local anesthesia after it is no longer needed.Lingering local anesthesia can be the cause of injuries due to biting ofthe tongue or lips. Lingering local anesthesia can also result in lossof productivity due to missed work hours. Lastly, lingering localanesthesia is an inconvenience and it is perceived as an annoyance bymany patients. The purpose of the present study was to determine whetherphentolamine-mesylate, an injectable alpha-adrenergic receptor agonist,which is FDA approved for the systemic treatment of hypertension inpheochromocytoma patients, rapidly reverses prolonged local anesthesiawhen injected locally at a very low concentration. Thephentolamine-mesylate concentration chosen for the present study was solow that it would be expected to lack systemic side-effects such assevere episodes of hypotension that have been described with the highsystemic drug doses which are approved by the FDA for the treatment ofhypertension in pheochromocytoma patients.

Study Design

[0053] The present human subjects study was designed to determinewhether injection of a physiological saline solution containing anextremely low concentration of phentolamine-mesylate is able toaccelerate the reversal of the effects of a previously injected localanesthetic agent containing an alpha-adrenergic receptor agonist. Aninjection of the physiological saline vehicle (withoutphentolarnine-mesylate) served as the control. In order to compare theeffects of phentolamine-mesylate to the vehicle in the same patient,bilateral local anesthesia injections were made into the mouth of thesame patient. This was followed by injection of thephentolamine-mesylate containing local anesthetic reversal agent (LARA)into one side of the oral cavity, and injection of the saline vehicle(control) solution into the opposite side of the oral cavity. The timeto reversal of the local anesthetic effect on both sides was thenrecorded to determine whether there is a difference between the twosides.

Drugs

[0054] The local anesthetic used was 2% polocaine (mepivacainehydrochloride) with levonordefrin (1:20,000 =0.05 mg /ml) (levonordefrininjection, USP) (Astra USA, Inc., Westborough, Mass. 01581).Levonordefrin is a sympathomimetic amine with a pharmacological profilesimilar to that of epinephrine, but with a lower potency. The localanesthetic reversal agent (LARA) was prepared as follows: A standardvial containing 5 mg of lyophilized phentolamine-mesylate for injection,USP (Bedford Laboratories, Bedford, Ohio 44146) was reconstituted with 1ml of physiological saline using a sterile, disposable 3 ml syringe anda sterile disposable hypodermic needle. After dissolution of thelyophilized powder, 0.5 ml of the phentolamine-mesylate solution waswithdrawn and injected into a 50 ml vial of physiological saline forinjection (USP) by means of a sterile disposable 3 ml syringe and asterile disposable hypodermic needle. The resulting LARA thus consistedof 0.05 mg /ml phentolamine-mesylate in physiological saline.

Methods

[0055] Three healthy, male human subjects, age 34-50, volunteered tohave local anesthetic injected in the mouth bilaterally under the lip inan easily repeatable location. The exact time of each injection wasrecorded. The position chosen was above (apical) the prominence of theroot of the upper cuspid teeth. This is a common site selected to numbthe cuspids, lateral incisors and upper lip. The volume of the localanesthetic injected was 1.7+0.1 ml on each side of the mouth. Twentyminutes after the local anesthetic was injected, each subject wasre-injected with 1.6 ml of LARA on one side and 1.6 ml of physiologicalsaline on the opposite side. A different size needle was used for theanesthetic and LARA or saline. A longer needle (1¼″) was used for thelocal anesthetic resulting in more solution being deposited around theinfra-orbital nerves. LARA or saline were injected with a shorter needle({fraction (1/2)}″) resulting in less LARA coming into contact with theanesthetic agent around the infra-orbital nerves. After all subjectsreceived anesthetic agent followed by LARA or saline, the subjects wereasked to test the intensity of numbness on both sides at the followingsites in the mouth and face: teeth, nose, upper lip and gingiva.Numbness of the teeth was tested by biting or grinding. Lip numbness wastested with the touch of the finger or tongue, and nose numbness wastested with the touch of the finger. Gingiva numbness was tested withthe blunt end of a wooden cotton swab.

Blinding

[0056] Two of the subjects (E and M) were blinded with respect to theside of the mouth where LARA or saline vehicle were injected, i.e. thesubjects were not told by the PI which side received LARA and which sidereceived saline vehicle. The third subject (H) was the PI of the studywho injected himself. As a consequence, subject H was not blinded withrespect to the side at which LARA or saline were injected.

Results

[0057] In all three subjects there was a dramatic acceleration of localanesthesia reversal on the side that had been injected with LARAcompared to the side that had been injected with saline. No side-effectsof any kind were noted in any of the three subjects. In general, feelingto the teeth returned first. Table 1 shows the times at which numbnessdisappeared and sensations re-appeared in the three subjects at thevarious sites on both sides of the mouth and face. In the early stagesof recovery the subjects reported that it was somewhat difficult todetermine which side of the lip was recovering first. In the laterstages of recovery, however, the differences between the two sides ofthe lip were profound and dramatic. In the other parts of the mouth andface, lateral differences were reported to be pronounced even in thevery early stages of recovery. The difficulty to sense lateraldifferences in the lips between the two sides early in the recoveryprocess is thought to be due to the following fact: The labial branchesof the infra-orbital nerve decussate at the midline, resulting in acrossover of innervation (and resulting sensation) at the midline of theupper lip. TABLE 1 Subject E - LARA on right hand side (RHS), Vehicle onLHS Recovery Time LHS Recovery Time RHS Site of anesthesia (Minutes)(Minutes) Teeth 80% Recovered Teeth 21 85 Teeth Fully Recovered 28 101Nose 30 143 Lip 41 83 Gingiva 46 141

[0058] Subject M - LARA on LHS, Vehicle on RHS Recovery Time LHSRecovery Time RHS Site of anesthesia (Minutes) (Minutes) Teeth 32 121Nose 40 163 Gingiva 45 102 Lip 36 178 All Sensation 58 229

[0059] Subject H - LARA on RHS, Vehicle on LHS Recovery Time LHSRecovery Time RHS Site of anesthesia (Minutes) (Minutes) Teeth 80%Recovered 19 201 Teeth 100% Recovered 27 218 Gingiva 42 137 Lip 37 226Nose 25 140 All Sensation 58 263

Conclusion

[0060] LARA had a profoundly faster effect on removing the numbnessassociated with local anesthesia than using physiological saline. Thetotal amount of phentolamine-mesylate contained in the administered LARAsolution was 0.08 mg (1.6 ml of a 0.05 mg /ml solution). This total doseof phentolamine-mesylate is approximately 62 times lower than the 5 mgdose approved by the FDA for systemic treatment of hypertension inpheochromocytoma patients (1 ml of a 5 mg /ml solution) and which cancause severe episodes of hypotension in normal patients. At theextremely low efficacious doses found to be effective in the presentstudy, any systemic side effects, such as those that can occur with theFDA-approved high dose, are likely to be absent. Indeed, in the presentstudy, no side-effects of any kind were noted during or afteradministration of 0.05 mg /ml phentolamine-mesylate.

[0061] Having now fully described this invention, it will be understoodby those of ordinary skill in the art that the same can be performedwithin a wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents, patent applications and publicationscited herein are fully incorporated by reference herein in theirentirety.

What is claimed is:
 1. A method of providing local anesthesia to amammal, comprising: (a) administering to said mammal in need thereof ananesthetic agent and an alpha adrenergic receptor agonist to the site tobe anesthetized, wherein said anesthetic agent is administered in anamount effective to provide local anesthesia and said alpha adrenergicreceptor agonist is administered in an amount effective to constrict theblood vessels at the site and prolong the local anesthesia, and then (b)administering a low dose of an alpha adrenergic receptor antagonist tosaid site to reduce the prolongation.
 2. The method according to claim 1, wherein anesthetic agent and alpha adrenergic receptor agonist areadministered together in solution.
 3. The method according to claim 2 ,wherein said solution is administered by injection into the site.
 4. Themethod according to claim 1 , wherein the anesthetic agent and alphaadrenergic receptor agonist are administered together in solution from acarpule, by injection into the site.
 5. The method according to claim 1, wherein said anesthetic agent is selected from the group consisting oflidocaine, polocaine, etidocaine, lignocaine, xylocaine, novacaine,carbocaine, procaine, prilocaine, bupivacaine, cinchocaine andmepivacaine.
 6. The method according to claim 1 , wherein the alphaadrenergic receptor agonist is a catecholamine or a catecholaminederivative.
 7. The method according to claim 6 , wherein the alphaadrenergic receptor agonist is levonordefrin, epinephrine ornorepinephrine.
 8. The method according to claim 1 , wherein said alphaadrenergic receptor antagonist is selected from the group consisting ofphentolamine, phentolamine hydrochloride, phentolamine mesylate,tolazoline, yohimbine, rauwolscine, doxazosine, labetolol, prazosine,tetrazosine and trimazosine.
 9. The method of claim 1 , wherein saidalpha adrenergic receptor antagonist is administered at a concentrationof from about 0.001 mg /ml to about 0.25 mg /ml.
 10. The method of claim1 , wherein at or below about 0.25 mg of said alpha adrenergic receptorantagonist is administered.
 11. The method of claim 1 , wherein about0.08 mg of said alpha adrenergic receptor antagonist is administered.12. The method according to claim 1 , wherein the alpha adrenergicreceptor antagonist is administered in solution from a carpule, byinjection into the site.
 13. The method according to claim 1 , whereinsaid alpha adrenergic receptor antagonist is administered topically tothe site.
 14. A method of providing local anesthesia to a human,comprising: (a) administering to said human in need thereof by injectionto the site to be anesthetized a solution comprising polocaine andlevonordefrin, wherein said polocaine is administered in an amounteffective to provide local anesthesia and said levonerdefrin isadministered in an amount effective to constrict the blood vessels atthe site and prolong the local anesthesia, thereby producing localanesthesia at said site, (b) carrying out a medical procedure on saidhuman, and then (c) administering about 0.08 mg of phentolamine mesylateat said site at a concentration of about 0.05 mg /ml to reduce theprolongation.
 15. The method according to claim 14 , wherein anestheticagent, alpha adrenergic receptor agonist, and alpha adrenergic receptorantagonist are administered in solution from a carpule, by injectioninto the site.
 16. A method of enhancing the survival of a tissue graft,comprising (a) administering to a mammal undergoing a tissue graft ananesthetic agent and an alpha adrenergic receptor agonist to the site ofthe tissue graft, wherein said anesthetic agent is administered in anamount effective to provide local anesthesia and said alpha adrenergicreceptor agonist is administered in an amount effective to constrict theblood vessels at the site and prolong the local anesthesia, (b)performing the tissue graft procedure, and then (c) administering analpha adrenergic receptor antagonist to said site to reduce theprolongation and enhance the tissue graft survival.
 17. The method ofclaim 16 , wherein said tissue graft is a hair graft.
 18. The method ofclaim 16 , wherein a low dose of alpha adrenergic receptor antagonist isadministered to the site
 19. The method of claim 16 , further comprising(d) administering hyaluronidase to the site after the tissue graftprocedure.
 20. The method of claim 19 , wherein said hyaluronidase isadministered by injection and wherein said hair graft is a hair flap.21. A method of providing a regional anesthetic block to a mammal,comprising: (a) administering to the mammal in need thereof ananesthetic agent and an alpha adrenergic receptor agonist in the site toreceive the anesthetic block, wherein said anesthetic agent isadministered in an amount effective to provide local anesthesia and saidalpha adrenergic receptor agonist is administered in an amount effectiveto constrict the blood vessels in the site and prolong the anestheticblock, and then (b) administering an alpha adrenergic receptorantagonist to said site to reduce the prolongation.
 22. The method ofclaim 21 , wherein a low dose of the alpha adrenergic receptorantagonist is administered.
 23. The method of claim 21 , wherein saidsite is the epidural space.
 24. A kit comprising a carrier means havingin close confinement therein two or more container means, wherein afirst container means contains an anesthetic agent and optionally analpha adrenergic receptor agonist and a second container means containsa low dose of an alpha adrenergic receptor antagonist.
 25. The kit ofclaim 24 , wherein said anesthetic agent and said alpha adrenergicreceptor agonist are in said first container means.
 26. The kit of claim24 , wherein said anesthetic agent and said alpha adrenergic receptoragonist are in separate container means.
 27. The kit of claim 24 ,wherein said container means is a carpule.
 28. The kit of claim 24 ,wherein said anesthetic agent is polocaine, said adrenergic receptoragonist is levonordefrin, and said alpha adrenergic receptor antagonistis phentolamine mesylate.
 29. The kit of claim 24 , wherein said alphaadrenergic receptor antagonist is phentolamine mesylate at a dose ofabout or less than 0.25 mg .
 30. The kit of claim 24 , wherein saidalpha adrenergic receptor antagonist is phentolamine mesylate at a doseof about 0.08 mg .
 31. The kit of claim 24 , further comprising acontainer means containing hyaluronidase.
 32. The kit of claim 24 ,wherein said container means containing said alpha adrenergic receptorantagonist further comprises hyaluronidase.